Genetic Causes of Oculocutaneous Albinism in Pakistani Population.

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes.

黑色素有助于保护我们的身体免受宽波长太阳辐射和皮肤癌的侵害。在人类的其他色素沉着紊乱病症中，据报道白化病有综合征型和非综合征型两种表现形式，且遗传模式多样。眼皮肤白化病（OCA）是一种常染色体隐性遗传的非综合征型白化病，表现为皮肤、毛发和虹膜中的黑色素部分或完全缺失。根据目前所有已发表的群体研究，到目前为止，已知OCA由7个不同基因的致病性变异引起。然而，导致OCA的等位基因检测率在50%到90%之间。揭示疾病病因背后的病理变异的重大挑战之一是家族间和家族内的基因座异质性。这个问题在高度近亲繁殖的人群中尤为突出。作为这种家族基因座异质性的实例，我们介绍了9个巴基斯坦近亲家庭，这些家庭中由于一个或两个不同的已知白化病相关基因的变异而出现OCA的遗传分离。所有已鉴定出的变异预计均为致病性变异，多种计算机算法以及与不同临床表型的关联都证实了这一点。我们报告了一名患有OCA的个体在TYR和OCA2基因中携带杂合的、可能致病的变异，这引发了双基因遗传可能性的问题。总之，我们的研究强调了外显子组测序对于近亲家庭完整基因诊断的重要性，并揭示了TYR和OCA2基因变异潜在的遗传相互作用和双基因遗传的影响。